Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Feb 25:13:2009-2024.
doi: 10.2147/CMAR.S296038. eCollection 2021.

MRPL13 Promotes Tumor Cell Proliferation, Migration and EMT Process in Breast Cancer Through the PI3K-AKT-mTOR Pathway

Miaomiao Cai  1 , Hanning Li  2 , Runfa Chen  1 , Xiang Zhou  1
Affiliations

MRPL13 Promotes Tumor Cell Proliferation, Migration and EMT Process in Breast Cancer Through the PI3K-AKT-mTOR Pathway

Miaomiao Cai et al. Cancer Manag Res. .

Abstract

Purpose: Breast cancer (BC), with varying histopathology, biology and response to systemic treatment, is the second leading cause of cancer-related mortality. Previous studies have inferred that the expression of mitochondrial ribosomal proteins (MRPs) is possibly related to the occurrence/progression of BC. MRPL13 might be one of the potential MRP candidates that are involved in BC tumorigenesis, but its role in BC has rarely been reported. The purpose of the current study was to evaluate the prognostic significance of MRPL13, as well as to explore its potential biological functions in BC.

Materials and methods: A series of bioinformatic and statistical methods were adopted to assess the MRPL13 expression profile, its relationship with clinicopathological characteristics, copy number variation (CNV), impact on clinical outcomes and relevant functions. All the results are analysed by 1097 BC patients collected from The Cancer Genome Atlas (TCGA) dataset and 52 clinical samples for immunohistochemistry (IHC) assay.

Results: The results demonstrated that the expression of MRPL13 in BC tissues was remarkably elevated than that in normal breast tissues. In addition, the Kaplan-Meier curves and Cox model indicated that patients with high MRPL13 expression were connected to a worse prognosis, heralding the independent prognostic value of this protein in BC. Moreover, an enrichment analysis showed that MRPL13 was mainly involved in cell cycle/division-related, RNA processing (degradation/splicing), MYC targets and the MTORC1 pathways. In addition, RNA interference (RNAi)-mediated MRPL13 silencing remarkedly inhibited proliferation and migration as well as the expression of EMT-related genes of BC cells in vitro. Mechanistically, attenuation of MRPL13 significantly suppressed the phosphorylation of AKT and mTOR, which could be partially abolished by 740Y-P (a PI3K agonist).

Conclusion: Our results provide evidence for the first time that increased MRPL13 expression correlates with adverse clinicopathological variables and unfavorable clinical outcomes of BC patients. Knockdown of MRPL13 restrains the proliferation and migration potential and EMT process of BC through inhibiting PI3K/AKT/mTOR signaling pathway.

Keywords: MRPL13; PI3K-AKT-mTOR; biomarker; breast cancer; prognosis.

PubMed Disclaimer

Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
MRPL13 mRNA expression in BC. (A) Comparison of MRPL13 mRNA expression in BC and non-cancerous tissues in TGCA dataset. (B) Comparison of MRPL13 mRNA expression in 113 paired BC and adjacent non-cancerous tissues in TCGA dataset. Comparison of MRPL13 mRNA expression in BC and non-cancerous tissues in GEO series: GSE71053 (C), GSE120129 (D), GSE50567 (E), GSE21422 (F). **p<0.01; ****p<0.0001.
Figure 2
Figure 2
Assessment of the protein expression of MRPL13 in BC tissues and adjacent controls by IHC. (A) Representative photographs of MRPL13 staining in BC and adjacent normal breast tissues. (B) Histogram shows IHC score quantification of MRPL13 in BC and normal tissue groups (n=52). ***p<0.001.
Figure 3
Figure 3
Kaplan-Meier survival analysis of MRPL13 mRNA expression in BC patients. Correlation between MRPL13 and OS (A), RFS (B), and DMFS (C) from Kaplan-Meier plotter database. The impact of MRPL13 mRNA expression on OS (D) and RFS (E) of BC patients according to data from TCGA.
Figure 4
Figure 4
Effect of MRPL13 mRNA expression on OS of BC patients stratified by different clinical features. Subgroup analysis of group age <50 years (A), ≥50 years (B), IDC (C), ILC (D), stage I+II (E), stage III+IV (F), Luminal (G), Her-2 overexpression (H) and TNBC (I) subtypes.
Figure 5
Figure 5
Effect of MRPL13 mRNA expression on RFS of BC patients according to different clinical characteristics. Subgroup analysis of group age <50 years (A), ≥50 years (B), IDC (C), ILC (D), stage I+II (E), stage III+IV (F), Luminal (G), Her-2 overexpression (H) and TNBC (I) subtypes.
Figure 6
Figure 6
MRPL13 genomic alterations in BC. (A) Oncoprint of MRPL13 alterations in METABRIC cohort. The different types of genetic alterations are marked with different colors. (B) Comparison of MRPL13 expression in different CNV groups. Distribution of MRPL13 CNV frequency in different grade (C), stage (D) and cell proliferation level (E) subgroups. The percentage number above the bar denotes the proportion of patients with MRPL13 gain and amplification in this subgroup. (F) Correlation between MRPL13 CNV and OS. ***p<0.001.
Figure 7
Figure 7
Enrichment analysis by GSEA. The top five gene sets enriched in high-MRPL13 expression group in hallmark (A) and KEGG (B). The different gene sets are highlighted in different colors.
Figure 8
Figure 8
Effects of MRPL13 on proliferation and migration of BC cell lines. The Efficiency of siRNA against MRPL13 was determined by both qRT-PCR (A) and WB (B) analyses in MDA-MB-231 and T47D cell lines. (C) Cell proliferation was detected by using CCK8 assay in MDA-MB-231 and T47D cells. (D) Cell migration ability was assessed by wound-healing assay in MDA-MB-231 and T47D cells. The β-actin was used as the internal reference for both qRT-PCR and WB assays. Each test was conducted in triplicate. *p<0.05; **p<0.01; ***p<0.001.
Figure 9
Figure 9
MRPL13 induces EMT process by activating the Akt/mTOR signaling pathway in MDA-MB-231 and T47D cell lines. MDA-MB-231 and T47D cell lines were transfected with siMRPL13-A (100 μM) for 72hr. (A) The protein level of EMT-related proteins (E-cad, Vimentin, Snail-1 and Snail-2) and AKT/mTOR pathway associated proteins (AKT, p-AKT, mTOR, p-mTOR) was detected by Western blot. For MRPL13 siRNA mediated knockdown rescue experiment, cells were transfected independently or jointly with the siMRPL13-A (100 μM) and PI3K/AKT/mTOR-specific agonist 740Y-P (20 μg/mL). The expression of mTOR signaling and EMT-related proteins was then assessed by Western blot in MDA-MB-231 (B) and T47D (C) cell lines. The β-actin served as a loading control for all above experiments. The above data are representative of three independent experiments.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Wang S, Wang Y, Yu C. Characterization of the relationship between FLI1 and immune infiltrate level in tumour immune microenvironment for breast cancer. J Cell Mol Med. 2020. - PMC - PubMed
    1. Waks AG, Winer EP. Breast cancer treatment. JAMA. 2019;321(3):316. doi:10.1001/jama.2018.20751 - DOI - PubMed
    1. Kalimutho M, Nones K, Srihari S, Duijf PHG, Waddell N, Khanna KK. Patterns of genomic instability in breast cancer. Trends Pharmacol Sci. 2019;40(3):198–211. doi:10.1016/j.tips.2019.01.005 - DOI - PubMed
    1. Zheng M, Zhou Y, Yang X, et al. High GINS2 transcript level predicts poor prognosis and correlates with high histological grade and endocrine therapy resistance through mammary cancer stem cells in breast cancer patients. Breast Cancer Res Treat. 2014;148(2):423–436. doi:10.1007/s10549-014-3172-7 - DOI - PubMed
    1. Stefanovic S, Deutsch TM, Riethdorf S, et al. The lack of evidence for an association between cancer biomarker conversion patterns and CTC-status in patients with metastatic breast cancer. Int J Mol Sci. 2020;21(6):2161. doi:10.3390/ijms21062161 - DOI - PMC - PubMed

LinkOut - more resources